U.S. patent application number 10/086781 was filed with the patent office on 2002-09-19 for process for producing new oxazepine derivatives.
This patent application is currently assigned to AJINOMOTO CO. INC. Invention is credited to Ezaki, Junko, Matsuzawa, Toshihiro, Sekiyama, Takaaki, Yamamoto, Takashi, Yatagai, Masanobu.
Application Number | 20020133004 10/086781 |
Document ID | / |
Family ID | 17205836 |
Filed Date | 2002-09-19 |
United States Patent
Application |
20020133004 |
Kind Code |
A1 |
Sekiyama, Takaaki ; et
al. |
September 19, 2002 |
Process for producing new oxazepine derivatives
Abstract
A process for producing a 5-substituted-5,11-dihydro-debenzo
[b,e] [1,4] oxazepine compound, wherein a
[2-(2-bromobenzyloxy)phenyl]amide derivative having a substituent
introduced through amido bond, the substituent locating at the
5-position of the final compound, as the starting material, is
subjected to the intramolecular arylation and then the obtained
product is reduced. In particular, (R)-1-[(4-methoxyphenyl)a-
cetyl]pyrrolidine-2-carboxylic acid [2-(2-bromo
benzyloxy)phenyl]amide is subjected to the intramolecular arylation
to obtain
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-
-yl]-2-(4-methoxyphenyl)ethanone and then this product is
reduced.
Inventors: |
Sekiyama, Takaaki;
(Kawasaki-Shi, JP) ; Matsuzawa, Toshihiro;
(Yokkaichi-Shi, JP) ; Yamamoto, Takashi;
(Kawasaki-Shi, JP) ; Yatagai, Masanobu;
(Kawasaki-Shi, JP) ; Ezaki, Junko; (Kawasaki-Shi,
JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
AJINOMOTO CO. INC
Tokyo
JP
|
Family ID: |
17205836 |
Appl. No.: |
10/086781 |
Filed: |
March 4, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10086781 |
Mar 4, 2002 |
|
|
|
PCT/JP00/05967 |
Sep 1, 2000 |
|
|
|
Current U.S.
Class: |
540/550 |
Current CPC
Class: |
C07D 413/12 20130101;
C07D 267/18 20130101; C07D 413/06 20130101; C07D 207/16 20130101;
C07D 413/14 20130101 |
Class at
Publication: |
540/550 |
International
Class: |
C07D 291/08 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 3, 1999 |
JP |
11-250298 |
Claims
What is claimed is:
1. A process for producing a
5-substituted-5,11-dihydro-dibenzo[b,e]1,4]ox- azepine compound
having the formula (3) or a stereoisomer thereof: 11wherein:
Y.sup.1 is hydrogen; Y.sup.2 is hydrogen or lower alkyl, or Y.sup.1
and Y.sup.2 together represent --CH.sub.2--CH.sub.2--CH.sub.2 or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2; Y.sup.3 is
--CH.sub.2--;--or --CH.sub.2--CH; and R.sup.1 to R.sup.5 are each
the same or different from one another and each represents
hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxyl, amino or
lower alkylamino, or R.sup.1 and R.sup.2, R.sup.2 and R.sup.3,
R.sup.3 and R.sup.4 or R.sup.4 and R.sup.5 together form
--OCH.sub.2O--; which process comprises the steps of: a)
intramolecularly arylating a [2-(2-bromobenzyloxy)phenyl]amide
compound of the formula (1): 12wherein Y.sup.1, Y.sup.2 and Y.sup.3
and R.sup.1 to R.sup.5 are as defined above; to form a
5,11-dihydro-dibenzo[b,e][1,4]- oxazepine compound of the formula
(2): 13wherein Y.sup.1, Y.sup.2 and Y.sup.3 and R.sup.1 to R.sup.5
are as defined above; and b) reducing the compound of the formula
(2).
2. The process of claim 1, wherein the
[2-(2-bromobenzyloxy)phenyl]amide compound of the formula (1) is
(R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine- -2-carboxylic
acid[2-(2-bromo benzyloxy)phenyl]amide of the formula (4): 14the
5,11-dihydro-dibenzo[b,e][1,4]oxazepine compound having the formula
(2) is
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrol-
idin]-1-yl]-2-(4-methoxyphenyl)ethanone of the formula (5): 15and
the 5-substituted-5,11-dihydro-dibenzo[b,e][1,4]oxazepine compound
of the formula (3) or the stereoisomer thereof is
(R)-(+)-5,11-dihydro-5-[1-(4-m-
ethoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]-oxazepine
of the formula (6): 16
3. The process of claim 2, which comprises the steps of
crystallizing
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-
-yl]-2-(4-methoxyphenyl)ethanone of the above formula (5) obtained
by the intramolecular arylation, isolating and then reducing the
resulting crystals.
4. The process of claim 1, wherein Y.sup.2 is C.sub.1-C.sub.4
alkyl.
5. The process of claim 1, wherein Y.sup.3 is --CH.sub.2--.
6. The process of claim 1, wherein the compound of the formula (1)
is dissolved in a solvent.
7. The process of claim 6, wherein the solvent comprises toluene,
pyridine, picoline, ethylpyridine, DMF or diphenyl ether.
8. The process of claim 1, wherein step (a) is effected in the
presence of a metal catalyst and an inorganic base under inert gas
at a temperature of about 100 to 150.degree. C.
9. The process of claim 8, wherein the metal catalyst is cuprous
bromide, the inorganic base is potassium carbonate and the solvent
is pyridine or picoline.
10. The process of claim 1, which further comprises crystallizing
the compound of the formula (2) prior to reduction step (b).
11. The process of claim 10, wherein the crystallization is
effected in toluene.
12. The process of claim 1, wherein step (b) comprises reducing the
compound of the formula (2) in a solvent by adding sodium
borohydride and boron trifluoride/tetrahydrofuran complex thereto
under inert gas at a temperature of from about 5 to 60.degree.
C.
13. The process of claim 12, wherein said solvent is
tetrahydrofuran.
14. A process for producing
(R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-
-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine of the following
formula (6), which comprises the steps of crystallizing
(R)-[[2-(5,11-dihydro-dib- enzo
[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)e-
thanone of the following formula (5), isolating and then reducing
the resulting crystals: 17
15. (R)-1-[(4-Methoxyphenyl)acetyl]pyrrolidine-2-carboxylic acid
[2-(2-bromobenzyloxy)phenyl]amide of the formula (4): 18
16.
(R)-[[2-(5,11-Dihydro-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin-
]-1-yl]-2-(4-methoxyphenyl)ethanone of the formula (5): 19
17. Crystals of
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4oxazepine-5-carbonyl-
)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone.
18. The crystals of claim 17, which satisfy at least one of the
following conditions a and b: a: melting point: 132 to 134.degree.
C., and b: powder X ray crystal analysis: 2.theta.=7.9.degree.
9.0.degree. 14.4.degree. 23.8.degree.
19. The crystals of claim 17, which satisfy at least one of the
following conditions a and b: a: melting point: 148 to 150.degree.
C., and b: powder X ray crystal analysis: 2.theta.=12.5.degree.
18.5.degree. 19.3.degree. 21.1.degree. 21.4.degree.
20. The crystals of claim 18, which satisfy both conditions a and
b.
21. The crystals of claim 19, which satisfy both conditions a and
b.
22. A method of converting crystals of (R)-[[2-(5,11-dihydro
-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphen-
yl)ethanone which satisfy at least one of the following conditions
a and b: a: melting point: 132 to 134.degree. C., and b: powder X
ray crystal analysis: 2.theta.=7.9.degree. 9.0.degree. 14.4.degree.
23.8.degree. (crystals 1) into crystals which satisfy at least one
of the following conditions a and b: a: melting point: 148 to
150.degree. C., and b: powder X ray crystal analysis:
2.theta.=12.5.degree. 18.5.degree. 19.3.degree. 21.1.degree.
21.4.degree. (crystals 2) which comprises the steps of suspending
the crystals 1 in toluene and stirring the obtained suspension at
about 100 to 50.degree. C.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a process for producing
5-substituted-5,11-dihydrodibenzo[b,e][1,4]oxazepine compounds
antagonistic to calcium channels and useful for treating or
preventing abnormal motor functions of the gastrointestinal tract,
particularly intestinal diseases, such as irritable bowel syndrome.
In particular, the present invention relates to a process for
producing
5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][-
1,4]oxazepine.
[0003] 2. Description of the Background
[0004] Certain 5-substituted-5,11-dihydrodibenzo[b,e][1,4]oxazepine
compounds are known to be antagonistic to calcium channels and
useful for treating or preventing abnormal motor functions of the
gastrointestinal tract, particularly intestinal diseases such as
irritable bowel syndrome. See WO 97/33885, WO 99/12925 and WO
00/40570. For example, WO 97/33885 discloses
(R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylme-
thyl]dibenzo[b,e][1,4]oxazepine having the formula (6): 1
[0005] Although the process described below for synthesizing
(R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]diben-
zo[b,e]-[1,4]oxazepine (6) is also disclosed, this process has the
drawback that by reacting starting material
5,11-dihydrodibenzo[b,e][1,4]- oxazepine (7) with
(S)-(+)-3-chloro-1-(4-methoxyphenethyl)piperidine (8), a large
amount of (S)-5,11-dihydro-5-[1-[2-(4-methoxyphenyl)ethyl]piperid-
in-3-yl]dibenzo[b,e][1,4]oxazepine (9) is produced as a by-product
in addition to the intended compound of the formula (6) and,
therefore, a complicated industrial purification method, such as
column chromatography is required: 2
[0006] Further, EP 404359 discloses a process for producing a
compound which is the same as that of the formula (6) except that
the oxazepine portion is replaced with thiazepine. Referring to the
method described in EP 404359, an attempt was made to obtain the
intended compound (6) by reducing a compound of the following
formula (4) to produce
(R)-2-(2-bromobenzyloxy)-N-[[1-[2-(4-methoxyphenyl)ethyl]pyrrolidin-2-yl]-
methyl]aniline (10) and then converting this product by
intramolecular arylation. However, a large amount of
(R)-2-[N-[[1-[2-(4-methoxyphenyl)et-
hyl]pyrrolidin-2-yl]methyl]amino]phenol (11) was produced as a
by-product in the reduction step, thereby making the efficient
production of the intended compound impossible. 3
SUMMARY OF THE INVENTION
[0007] Accordingly, it is an object of the present invention to
provide an industrially useful process for producing
5-substituted-5,11-dihydrodiben- zo [b,e][1,4]oxazepine compounds,
particularly 5,11-dihydro-5-[1-(4-methox-
yphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine.
[0008] It is also an object of the present invention to provide
useful intermediates for producing
5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrr-
olidinylmethyl]dibenzo[b,e][1,4]oxazepine.
[0009] The above objects and others are provided by a process for
producing a 5-substituted-5,11-dihydrodibenzo [b,e][1,4]oxazepine
compound having the formula (3) or a stereoisomer thereof: 4
[0010] wherein: Y.sup.1 is hydrogen; Y.sup.2 is hydrogen or lower
alkyl, or Y.sup.1 and Y.sup.2 together represent
--CH.sub.2--CH.sub.2--CH.sub.2-- - or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--; Y.sup.3 represents
--CH.sub.2;-- or --CH.sub.2--CH--; and R.sup.1 to R.sup.5 are the
same or different from one another and each represents hydrogen,
halogen, lower alkyl, hydroxyl, lower alkoxyl, amino or lower
alkylamino, or R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, R.sup.3
and R.sup.4 or R.sup.4 and R.sup.5 together form
--OCH.sub.2O--;
[0011] which process entails the steps of:
[0012] a) intramolecularly arylating a
[2-(2-bromobenzyloxy)phenyl]amide compound of the formula (1):
5
[0013] wherein Y.sup.1, Y.sup.2 and Y.sup.3 and R.sup.1 to R.sup.5
are as defined above;
[0014] to form a 5,11-dihydrodibenzo[b,e][1,4]oxazepine compound of
the formula (2): 6
[0015] wherein Y.sup.1, Y.sup.2 and Y.sup.3 and R.sup.1 to R.sup.5
are as defined above; and
[0016] b) reducing the compound of the formula (2).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] In accordance with the present invention, it has now been
discovered that the intended
5-substituted-5,11-dihydrodibenzo[b,e][1,4]o- xazepine compounds
(3) can be efficiently obtained by incorporating a substituent in
the 5-position, into the molecule through an amido bond to obtain a
compound of the formula (1), then converting this compound into a
compound of the formula (2) by intramolecular arylation, and
finally reducing the compound of the formula (2).
[0018] Thus, the present invention provides a process for producing
5-substituted-5,11-dihydrodibenzo[b,e][1,4]oxazepine compounds
having the formula (3) and stereoisomers thereof: 7
[0019] wherein Y.sup.1 represents hydrogen atom; Y.sup.2 represents
hydrogen atom or a lower alkyl group, or Y.sup.1 and Y.sup.2
together represent --CH.sub.2--CH.sub.2--CH.sub.2-- or
--CH.sub.2--CH.sub.2--CH.su- b.2--CH.sub.2--, Y.sup.3 represents
--CH.sub.2-- or --CH.sub.2--CH.sub.2--, and R.sup.1 to R.sup.5 are
the same or different from one another and each represents hydrogen
atom, a halogen atom, a lower alkyl group, hydroxyl group, a lower
alkoxyl group, amino group or a lower alkylamino group, or
R.sup.1and R.sup.2, R.sup.2 and R.sup.3, R.sup.3 and R.sup.4 or
R.sup.4 and R.sup.5 together form --OCH.sub.2O--which process
entails the steps of intramolecularly arylating a
[2-(2-bromobenzyloxy)phenyl]amide compound of the above-mentioned
formula (1) to form a 5,11-dihydrodibenzo[b,e][1,4]oxazep- ine
compound of the above-mentioned formula (2), and reducing the
compound of the formula (2).
[0020] The present invention also provides a process for producing
(R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]-dibe-
nzo[b,e][1,4]oxazepine represented by the following formula (6),
which entails the steps of intramolecularly-arylating
(R)-1-[(4-methoxyphenyl)a- cetyl]pyrrolidine-2-carboxylic acid
[2-(2-bromo-benzyloxy)phenyl]amide of the following formula (4) to
form (R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]o-
xazepine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone
of the following formula (5), and reducing this compound: 8
[0021] The present invention also provides a process wherein, in
the process for producing the compound of above formula (6),
(R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1--
yl]-2-(4-methoxyphenyl)ethanone of the above formula (5) is
crystallized, and then the crystals are isolated.
[0022] The present invention further provides
(R)-1-[(4-methoxyphenyl)acet- yl]pyrrolidine -2-carboxylic
acid[2-(2-bromo-benzyloxy)phenyl]amide of the above formula (4)
which is an important starting material for the compound of the
above formula (6), (R)-[[2-(5,11-dihydro
-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphen-
yl)ethanone of the above formula (5) which is also an important
intermediate, and crystals thereof.
[0023] The lower alkyl groups and also the lower alkyl groups in
the lower alkylamino groups in the above formulae are linear or
branched lower alkyl groups having 1 to about 8 carbon atoms,
preferably 1 to about 4 carbon atoms. The lower alkoxyl groups are
linear or branched lower alkoxyl groups having 1 to about 8 carbon
atoms, preferably 1 to about 4 carbon atoms.
[0024] Preferably, Y.sup.1 and Y.sup.2 in the above formulae
together form --CH.sub.2--CH.sub.2--CH.sub.2--. Y.sup.3 is
preferably --CH.sub.2--. R.sup.1 to R.sup.5 are each the same or
different from one another and preferably each represents hydrogen
atom or a lower alkoxyl group. It is particularly preferred that
R.sup.1, R.sup.2, R.sup.4 and R.sup.5 each represents hydrogen atom
and R.sup.3 represents a lower alkoxyl group, particularly methoxyl
group.
[0025] The 2-(2-bromobenzyloxy)phenyl]amide compounds of the above
formula (1) used as the starting materials in the process of the
present invention are produced by condensing an N-acylamino acid
compound (12) with 2-(2-bromobenzyloxy)aniline (13) or a salt
thereof to form an amido bond. In the above formulae (1), (2) and
(3), the term "lower alkyl groups" means alkyl groups having 1 to
about 8 carbon atoms, the term "lower alkoxyl groups" means alkoxyl
groups having 1 to about 8 carbon atoms, and the term "lower
alkylamino groups" means alkylamino groups having 1 to about 8
carbon atoms. The halogen atoms are fluorine atom, chlorine atom,
or bromine atom, for example. For the condensation, a method
usually employed for the condensation reaction, such as acid
anhydride mixed method, active ester method or DCC method, can be
employed. 9
[0026] (R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic acid
[2-(2-bromobenzyloxy)phenyl]amide of the above formula (4) which is
one of the compounds of the formula (1) in the present invention
can be obtained by reacting D-proline (14) with
4-methoxyphenylacetyl chloride (15) to obtain
(R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic acid (16),
converting this compound into an acid anhydride mixture by a
conventional method, and further reacting this product with
2-(2-bromobenzyloxy)aniline hydrochloride (17) as shown by the
following reaction scheme. Although
(R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-ca- rboxylic acid
[2-(2-bromobenzyloxy)phenyl]amide (4) obtained by the reaction can
be directly used in the subsequent step, it is preferred to use
this compound after purification by, for example, crystallization.
10
[0027] The intended
5-substituted-5,11-dihydrodibenzo[b,e][1,4]oxazepine compounds of
the above formula (3) can be obtained by the intramolecular
arylation of the 2-(2-bromobenzyloxy)phenyl]amide compounds (1)
obtained as described above to obtain
5,11-dihydrodibenzo[b,e][1,4]oxazepine compounds of the above
formula (2) followed by the reduction of the obtained
compounds.
[0028] In the intramolecular arylation, the
[2-(2-bromo-benzyloxy)phenyl]a- mide compound (1) is dissolved in a
solvent, then a metal catalyst such as copper or its salt and a
suitable inorganic base are added to the obtained solution and the
reaction is carried out in an inert gas stream at a temperature of
100 to 150.degree. C. which varies depending on the boiling point
of the solvent for about 8 to 200 hours. The solvents include
toluene, pyridine, picoline, ethylpyridine, DMF, diphenyl ether,
etc. The inorganic bases include sodium carbonate, potassium
carbonate, etc. Preferably, the intramolecular arylation reaction
is carried out by using cuprous bromide as the catalyst, 1 to 3
equivalents of potassium carbonate and pyridine or picoline as the
solvent in an inert gas stream at 115 to 140.degree. C. for 10 to
100 hours.
[0029] The reaction mixture containing 5,11-dihydrodibenzo
[b,e][1,4]oxazepine compound (2) obtained by the above-described
reaction can be subjected to the subsequent reaction after the
purification of the product by the extraction, silica gel
chromatography or the like or, on the other hand, the reaction
mixture can be directly used for the subsequent reaction. The
purity of the intended final compound can be improved by
crystallizing (R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepine-
-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl) ethanone (5)
which is one of the compounds of the formula (2) of the present
invention. The crystallization is conducted by, for example,
dissolving a residue, containing the compound of the formula (5)
obtained by the extraction from the reaction mixture, in a solvent
such as toluene and then cooling the obtained solution to form the
crystals. In this step, the compound of the formula (5) is
dissolved in the solvent to obtain a solution having a
concentration of 40 to 50% by weight and then the crystallization
is conducted at 20 to 30.degree. C., to obtain the crystals
(crystals 1). When the compound of the formula (5) is dissolved in
toluene to obtain a solution having a concentration of 10 to 30% by
weight and then the obtained solution is cooled to 10.degree. C.,
other crystals can be obtained (crystals 2). The crystals 1 are
formed in the form of glassy, flaky crystals on the walls of the
vessel, while the crystals 2 are formed in the form of a suspension
of fine particles. The crystals 1 can be converted into the
crystals 2 by suspending crystals 1 in toluene and stirring the
obtained suspension at about 10 to 50.degree. C.
[0030] The subsequent reduction reaction can be conducted by
dissolving the 5,11 -dihydrodibenzo[b,e][1,4]oxazepine compound (2)
obtained as described above in a solvent and adding sodium
borohydride and boron trifluoride/tetrahydrofuran complex to the
obtained solution. As for the reaction conditions, the reaction is
to be conducted in an inert gas stream at 5 to 60.degree. C. for 4
to 70 hours. The solvents are ethers such as tetrahydrofuran. The
solvent may contain 0 to 50% of toluene. Preferably, a suspension
of 3 to 6 equivalents of sodium borohydride in tetrahydrofuran is
cooled to 0 to 10.degree. C. and then a solution of a compound of
the formula (2) in tetrahydrofuran is added to the suspension. 4 to
6 equivalents of boron trifluoride/tetrahydrofuran complex is added
dropwise to the obtained solution, and they are stirred at 0 to
10.degree. C. for 1 to 20 hours and then at 30 to 40.degree. C. for
10 to 60 hours. The intended
5-substituted-5,11-dihydro-dibenzo[b,e][- 1,4]oxazepine compound
(3) can be obtained by adding 6 to 8 equivalents of an aqueous
sodium hydroxide solution to the reaction mixture, stirring the
obtained mixture at 50 to 60.degree. C. for 1 to 4 hours,
extracting the product from the reaction mixture and purifying it
by silica gel column chromatography or the like. The compound of
the formula (3) extracted from the reaction mixture can be obtained
in the form of crystals of a salt thereof with a suitable acid. The
salt is, for example, the hydrochloride.
[0031] Reference will now be made to certain Examples which are
provided solely for purposes of illustration and are not intended
to be limitative.
EXAMPLES
[0032] The conditions of the liquid chromatography in the analysis
were as follows:
[0033] Column: YMC-Pack ODS-AM AM-302 4.6 mm I.D..times.150 mm
[0034] Solvent: A: 0.1% trifluoroacetic acid B: acetonitrile
A:B=60:40.fwdarw.8:82/35 min
[0035] Flow rate: 1 mL/min
[0036] Detection method: UV 254 nm
[0037] Column temperature: 40.degree. C.
[0038] Injection volume: 10 .mu.L
REFERENTIAL EXAMPLE 1
Preparation of
(R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic acid
(16)
[0039] D-proline (430 g, 3.73 mol) was dissolved in water (4.30 L).
Acetone (2.15 L) and 6 M aqueous sodium hydroxide solution (0.645
L) were added to the obtained solution. The solution was cooled to
5.degree. C. and then a solution of 4-methoxyphenylacetyl chloride
(696 g, 3.73 mol) in acetone (1.29 L) was added dropwise thereto.
In this step, 6 M aqueous sodium hydroxide solution was also added
dropwise thereto to keep pH in the range of 13 to 14. After the
completion of the addition, the reaction mixture was concentrated
to a volume of about 5.5 L under reduced pressure. The obtained
concentrate was added dropwise to 6 M hydrochloric acid (1.29 L),
and the resultant mixture was stirred overnight. The crystals thus
obtained were filtered to obtain (R)-1-[(4-methoxyphenyl)ac-
etyl]pyrrolidine-2-carboxylic acid (953 g, 95%).
[0040] .sup.1H NMR (CDCl.sub.3) .delta.1.93-2.11(m,3H), 2.32(m,1H),
3.48(m,1H), 3.59(m,1H), 3.67(s,2H), 3.78(s,3H), 4.58(m,1H),
6.86(d-like,2H), 7.18(d-like,2H), 9.90(br,1H).
[0041] .sup.13C NMR (CDCl.sub.3) .delta.24.8, 27.5, 40.8, 47.9,
55.3, 60.0, 114.2, 125.3, 130.0, 158.7, 172.6, 173.2. ESI MASS m/z
(MH.sup.+) 264.
Example 1
Preparation of
(R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic
acid[2-(2-bromobenzyloxy)phenyl]amide (4)
[0042] (R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic acid
(953 g, 3.55 mol) obtained in Referential Example 1 was suspended
in ethyl acetate (12.1 L). The obtained suspension was cooled to
5.degree. C. and then N-methylmorpholine (441 mL, 4.01 mol) was
added to the suspension. Ethyl chloroformate (373 mL, 3.90 mol) was
added dropwise to the reaction mixture while it was kept at a
temperature of not higher than 10.degree. C. After the completion
of the addition, the reaction mixture was stirred at 5.degree. C.
for 1 hour. 2-(2-Bromobenzyloxy)aniline hydrochloride (1.19 kg,
3.55 mmol) was added to the obtained solution, and the reaction
mixture was stirred at 5.degree. C. for 1 hour. Then the
temperature of the obtained reaction mixture was elevated to
25.degree. C., and the mixture was stirred for 2 hours. Water (3.74
L) was added to the reaction mixture to wash the mixture. The
organic layer thus obtained was further washed with water. The
obtained organic layer was concentrated under reduced pressure.
Heptane was added to the obtained concentrate, and they were
stirred at room temperature overnight. The crystals thus obtained
were collected by the filtration to obtain
(R)-1-[(4-methoxyphenyl)acetyl- ]pyrrolidine-2-carboxylic acid
[2-(2-bromobenzyloxy)phenyl]amide (1.69 kg, 90%).
[0043] .sup.1H NMR (CDCl.sub.3) .delta.1.82-2.03(m,2H), 2.12(m,1H),
2.47(m,1H), 3.40-3.60(m,4H), 3.75(s,3H), 4.78(dd,J=8.0,1.7 Hz,1H),
5.17(s,2H), 6.78(d-like,J=8.6 Hz,2H), 6.87(dd,J=7.5,1.6 Hz,1H),
6.93-7.03(m,2H), 7.10(d-like,J=8.6 Hz,2H), 7.19(m,1H),
7.28(dt,J=7.5,1.3 Hz,1H), 7.55-7.62(m,2H), 8.35(dd,J=7.4,2.2
Hz,1H), 9.27(br,1H).
[0044] .sup.13C NMR (CDCl.sub.3) .delta.25.0, 27.6, 40.7, 47.6,
55.2, 60.9, 70.3, 111.8, 114.0, 120.4, 121.5, 123.8, 126.1, 127.7,
129.4, 129.5, 130.0, 132.6, 135.9, 147.2, 158.5, 169.3, 171.5. ESI
MASS m/z (M.sup.+) 523.
Example 2
Preparation of (R)-[[2-(5,11-dihydrodibenzo
[b,e][1,4]oxazepine-5-carbonyl-
)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (5)
[0045] (R)-1-[(4-Methoxyphenyl)acetyl]pyrrolidine-2-carboxylic acid
[2-(2-bromobenzyloxy)phenyl]amide (1.69 kg, 3.20 mol), cuprous
bromide (23.0 g, 0.16 mol) and potassium carbonate (443 g, 3.20
mol) were added to pyridine (4.19 L), and the mixture was stirred
under reflux in nitrogen atmosphere for 100 hours. After cooling to
room temperature, toluene (8.4 L) was added to the reaction
mixture. After washing the mixture with 6 M hydrochloric acid (9.17
L, 55.0 mol), the obtained organic layer was successively washed
with 1 M hydrochloric acid, saturated aqueous sodium
hydrogencarbonate solution and water. The organic layer was dried,
the solvent was evaporated under reduced pressure, and the obtained
residue was subjected to silica gel column chromatography and then
eluted with a solvent mixture of ethyl acetate and hexane (3:2) to
obtain (R)-[[2-(5,11-dihydro -dibenzo[b,e][1,4]oxazep-
ine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (1.35
kg, 95%) in the form of a colorless oil.
[0046] .sup.1H NMR (CDCl.sub.3) .delta.1.7-2.4(m,4H),
3.4-3.9(m,4H), 3.77(s,3H), 4.7-4.8(m,2H), .cndot.5.73(m,1H),
6.4(m,1H), 6.7-7.6(m,11H). ESI MASS m/z 443 (MH.sup.+), 465
(M+Na.sup.+).
Example 3
Preparation of
(R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidin-
ylmethyl]dibenzo[b,e][1,4]oxazepine (6) hydrochloride
[0047] Sodium borohydride (400 g, 10.57 mol) was suspended in
tetrahydrofuran (10.77 L), and the obtained suspension was cooled
to 5.degree. C. A solution of (R)-[[2-(5,11-dihydro
-dibenzo[b,e][1,4]oxazep-
ine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (1.35
kg, 3.04 mol) in tetrahydrofuran (2.69 L) was added to the
suspension in nitrogen atmosphere. Boron
trifluoride/tetrahydrofuran complex (1.97 kg, 14.10 mol) was added
dropwise to the obtained mixture while the temperature was kept at
10.degree. C. or lower. After the completion of the addition, the
reaction mixture was stirred at 5.degree. C. for 1 hour and then
the temperature was elevated to 40.degree. C., and the mixture was
stirred for 14 hours. After cooling to 5.degree. C., 1.5 M aqueous
sodium hydroxide solution (13.6 L) was added dropwise to the
reaction mixture. After the completion of the addition, the
reaction mixture was stirred at 60.degree. C. for 2 hours. The
solution was cooled to room temperature. After the extraction with
toluene (8.1 L), the obtained organic layer was concentrated to a
volume of about 7.5 L under reduced pressure, and then washed with
water 3 times. The temperature of the organic layer was elevated to
30.degree. C., to which 4 M hydrogen chloride/ethyl acetate
solution (0.941 L, 3.01 mol) was added dropwise, and the obtained
mixture was stirred at 5.degree. C. overnight. The crystals thus
formed were collected by the filtration and then recrystallized
from 2-propanol to obtain (R)-(+)-5,11
-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]-
oxazepine hydrochloride (1.00 kg, 73%) in the form of white
crystals.
[0048] The spectrum of this compound coincided with that given in
WO 97/33885.
Example 4
Preparation of crystals 1 of
(R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepi-
ne-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (5)
[0049] (R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic
acid[2-(2-bromobenzyloxy)phenyl]amide (1.26 kg, 2.40 mol), cuprous
bromide (17.3 g, 0.12 mol) and potassium carbonate (996 g, 7.20
mol) were added to 4-picoline (3.14 L), and the mixture was stirred
in nitrogen atmosphere at 130.degree. C. for 19 hours. After
cooling to room temperature, toluene (6.28 L) was added to the
reaction mixture and then 6 M hydrochloric acid (7.38 L, 44.3 mol)
was added thereto to wash it. The obtained organic layer was
successively washed with 1 M hydrochloric acid, saturated aqueous
sodium hydrogencarbonate solution and water. The organic layer was
concentrated at 25.degree. C. under reduced pressure to adjust the
concentration of (R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepi-
ne-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone to 50
wt. %. The solution was left to stand at room temperature
overnight. The yellowish white crystals of
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazep-
ine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (733
g, 69%) were obtained by the filtration. The area purity of
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-
-yl]-2-(4-methoxyphenyl)ethanone in HPLC was improved from 83.1% to
99.1% by the crystallization.
[0050] .sup.1H NMR (CDCl.sub.3) .delta.1.7-2.4(m,4H),
3.4-3.9(m,4H), 3.77(s,3H), 4.7-4.8(m,2H), 5.73(m,1H), 6.4(m,1H),
6.7-7.6(m,11H). ESI MASS m/z 443 (MH.sup.+), 465 (M+Na.sup.+).
Melting point: 132-134.degree. C. Powder X ray crystal analysis:
2.theta.=7.9.degree. 9.0.degree. 14.4.degree. 23.8.degree.
Example 5
Preparation of crystals 2 of
(R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepi-
ne-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (5)
[0051] (R)-1-[(4-methoxyphenyl)acetyl]pyrrolidine-2-carboxylic
acid[2-(2-bromobenzyloxy)phenyl]amide (1.07 kg, 2.00 mol), cuprous
bromide (14.4 g, 0.1 mol) and potassium carbonate (829 g, 6.00 mol)
were added to 4-picoline (2.62 L), and the mixture was stirred in
nitrogen atmosphere at 130.degree. C. for 20 hours. After cooling
to room temperature, toluene (5.23 L) was added to the reaction
mixture and then 6 M hydrochloric acid (6.15 L, 36.9 mol) was added
thereto to wash it. The obtained organic layer was successively
washed with 1 M hydrochloric acid, saturated aqueous sodium
hydrogencarbonate solution and water. The organic layer was
concentrated at 50.degree. C. under reduced pressure to adjust the
concentration of (R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepi-
ne-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone to 20
wt. %. The solution was stirred overnight and then cooled to
5.degree. C. The yellowish white crystals of
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazep-
ine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (733
g, 69%) thus formed were obtained by the filtration. The area
purity of
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-
-yl]-2-(4-methoxyphenyl)ethanone in HPLC was improved from 89.4% to
97.8% by the crystallization.
[0052] .sup.1H NMR (CDCl.sub.3) .delta.1.7-2.4(m,4H),
3.4-3.9(m,4H), 3.77(s,3H), 4.7-4.8(m,2H), 5.73(m,1H), 6.4(m,1H),
6.7-7.6(m,11H). ESI MASS m/z 443(MH.sup.+), 465 (M+Na.sup.+)
Melting point: 148-150.degree. C. Powder X ray crystal analysis:
2.theta.=12.5.degree. 18.5.degree. 19.3.degree. 21.1.degree.
21.4.degree.
Example 6
Transition of crystals 1 of
(R)-[[2-(5,11-dihydrodibenzo[b,e][1,4]oxazepin-
e-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (5) to
crystals 2 thereof
[0053] Crystals 1 of
(R)-[[2-(5,11-dihydro-dibenzo[b,e][1,4]oxazepine-5-ca-
rbonyl)pyrrolidin]-1-yl]-2-(4-methoxyphenyl)ethanone (1.34 g)
obtained in Example 4 was suspended in toluene (6 mL), and the
obtained suspension was stirred at 10.degree. C. for 47 hours. The
suspension was filtered to obtain yellowish white crystals 2 of
(R)-[[2-(5,11-dihydro
-dibenzo[b,e][1,4]oxazepine-5-carbonyl)pyrrolidin]-1-yl]-2-(4-methoxy-phe-
nyl)ethanone (1.04 g, 78%).
[0054] Thus, 5-substituted-5,11-dihydrodibenzo[b,e][1,4]oxazepine
compounds, in particular,
5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrol-
idinylmethyl]dibenzo[b,e][1,4]oxazepine, are obtained in a high
yield by the present invention, and an industrially useful process
is provided.
[0055] Having described the present invention, it will be apparent
to one of ordinary skill in the art that many changes and
modifications may be made to the above-described embodiments
without departing from the spirit and the scope of the present
invention.
* * * * *